Our new ecologic evidence from Northern Chile suggests that arsenic exposure in childhood or in utero could cause up to a 10-fold increase in lung cancer in young adults. This may be the first time that early-life exposure to a common environmental agent has been linked to such high risks of an adult cancer in humans. Although supported by intriguing animal data, these findings are preliminary and need to be confirmed. The highly unique arsenic exposure scenario in Northern Chile offers an excellent and rare opportunity to do this. Because almost everyone in Northern Chile obtains their water from large municipal sources, and past arsenic levels in all of these sources are well documented over the past 50 years or more, arsenic carcinogenicity can be studied using data on past exposure that are much more accurate than can be obtained anywhere else in the world. In addition, a very distinct 14-year period of high exposure in this area has created a population where tens of thousands of people were highly exposed only in utero and early childhood. As such, this area provides a unique opportunity to study the long-term impacts of an early-life carcinogen with excellent data on past exposure. We propose a case-control study of 675 lung and bladder cancer cases obtained over a three-year period using a rapid case ascertainment system involving all local pathologists. Controls will be obtained from the Chile electoral register which includes 94% of the Chile population. We will obtain dose-response information with data on past exposure that is more accurate than found in any previous study and that can be directly applied to US regulatory and public health decisions. Biological samples will be collected and susceptibility related to metabolism, diet, genetics, and other factors will also be investigated. We have found evidence that people producing high levels of monomethylated arsenic (MMA) may have 2-5 times higher cancer risks than others. Whether this is due to the rarely studied but highly toxic trivalent form (MMA3) will be explored and could provide new information on the primary toxic species of arsenic carcinogenesis. Millions of people in the US are exposed to drinking water arsenic. Current US arsenic regulations do not incorporate information on potentially susceptible subgroups despite the fact that cancer risks in these groups could be exceedingly high. The information gained from this project may help to determine if some people, such as children, pregnant women, those who metabolize arsenic poorly, or those with poor nutrition, may need special consideration in regulatory standard setting. Information on early-life exposure, MMA3, diet, and the future genetic and proteomic studies we will plan as part of this project could add further insight into the important co-factors and mechanisms of environmental carcinogenesis.